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Clinical and Surgical Management of VHL-Related Cysts and Cystic RCC

Mark W. Ball, MDAssistant Research Physician

Attending Surgeon

Urologic Oncology Branch, National Cancer Institute

@markballmd

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Outline

Prevalence of renal cysts and cystic RCC in VHL Biology of cystic VHL-related lesions Differentiating cysts from cystic RCC Surgical management

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VHL Renal Manifestations

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VHL Renal Manifestations

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VHL Renal Manifestations

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VHL Renal Manifestations

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Cyst vs Cystic RCC

Chen et al. 2012 Arch Pathol Lab Med

Atypical CystsBenign CystOne layer of clear cells Multiple layers and/or

focal papillary tufting

Cystic RCCCluster of clear cells associated with cyst

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CNS HB: central nervous system hemangioblastomas; RA: retinal angiomas, ELST: endolymphatic sac tumor; KS: kidney solid tumor;KC: kidney cyst, pheo: pheochromocytoma, PS: pancreatic solid tumor; PC: pancreatic cyst; ECA: epididymal cystadenoma

CNS HB RA ELST Kid Solid Kid Cyst Pheo PS PC ECA# evaluable 766 756 731 766 763 741 762 761 249

Total 606 (78.9) 400(52.9) 55 (7.5) 439 (57.3) 547 (71.7) 182 (24.6)

195 (25.6) 483 (63.5) 61 (24.5)

How prevalent are renal cysts in VHL?

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CNS HB RA ELST Kid Solid Kid Cyst Pheo PS PC ECA# evaluable 766 756 731 766 763 741 762 761 249

Total 606 (78.9) 400(52.9) 55 (7.5) 439 (57.3) 547 (71.7) 182 (24.6)

195 (25.6) 483 (63.5) 61 (24.5)

CNS HB: central nervous system hemangioblastomas; RA: retinal angiomas, ELST: endolymphatic sac tumor; KS: kidney solid tumor;KC: kidney cyst, pheo: pheochromocytoma, PS: pancreatic solid tumor; PC: pancreatic cyst; ECA: epididymal cystadenoma

How prevalent are renal cysts in VHL?

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CNS HB RA ELST Kid Solid Kid Cyst Pheo PS PC ECA# evaluable 766 756 731 766 763 741 762 761 249

Total 606 (78.9) 400(52.9) 55 (7.5) 439 (57.3) 547 (71.7) 182 (24.6)

195 (25.6) 483 (63.5) 61 (24.5)

Missense, n (%)n=376

262 (69.7) 195 (52.6) 16 (4.5) 180 (47.8) 234 (62.4) 150 (42.3)

109 (29.1) 171(45.6) 23 (19.7)

Partial Deletion, n (%)N=166

149 (89.8) 92 (56.1) 21 (13.2) 117 (79.5) 137 (83) 12 (7.3) 37 (22.4) 138 (83.6) 23 (36.)

Nonsense, n (%)N=64

62 (96.9) 42 (65.6) 9 (14.1) 48 (75) 55 (85.9) 5 (7.8) 16 (25.4) 58 (92.1) 7 (33.3)

Complete Deletion, n (%)N=49

40 (81.6) 9 (18.7) 0 17 (34.7) 29 (60.4) 0 7 (14.6) 36 (75) 1 (5.6)

Frameshift, n (%)N=60

51 (85) 35 (60.3) 4 (7.1) 43 (71.6) 49 (81.7) 3 (5) 15 (25) 39 (66.1) 5 (25)

Splice, n (%)N=31

26 (83.9) 16 (53.3) 4 (13.3) 20 (64.5) 24 (77.4) 8 (26.7) 8 (25.1) 24 (77.4) 2 (50)

AA Deletion, n (%)N=16

14 (87.5) 9 (56.3) 1 (6.25) 13 (81.3) 15 (93.8) 1 (6.25) 1 (6.25) 15 (93.7) 0

CNS HB: central nervous system hemangioblastomas; RA: retinal angiomas, ELST: endolymphatic sac tumor; KS: kidney solid tumor;KC: kidney cyst, pheo: pheochromocytoma, PS: pancreatic solid tumor; PC: pancreatic cyst; ECA: epididymal cystadenoma

How prevalent are renal cysts in VHL?

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Range of Phenotypes

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How do cystic lesions behave?

Limited published data on behavior of cystic VHL tumors Must extrapolate from: Sporadic cystic RCC

Solid VHL tumors

Institutional experience

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Cyst Biology: CAIX staining

Mandriota et al, Cancer Cell, 2002Are any cysts truly benign?

Normal Kidney (-) Tumor (+) Cyst lining (+)

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Evolution of a complex cystic lesion

2014 2016 2017 2018

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How do sporadic cystic lesions behave?

336 patients with complex renal cystsOnly 60 patients had surgeryMean cyst size 3.5 cm1 cancer-specific death

• 133 patients with resected complex renal cysts• 76% low grade, low stage• 1 local recurrence

Reese et al Urologic Oncology, 2012 Chandrasekar et al J Urol, 2017

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Growth Kinetics in VHL-Associated Solid Renal Tumors

Ball et al Under Review

240 tumors in 152 patients, comprising 1301 tumor measurements

Median GR: 3.7 mm/yr (IQR: 2.6-5.7)

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Solid tumors: No patients developed metastatic disease when managed by the 3 cm guideline.

Tumor Size # mets/ # pts (%)< 3 cm 0/178 (0%)3-4 cm 4/109 (3.7%)4-5 cm 8/62 (12.9%)5-6 cm 7/27 (25.9%)6-7 cm 6/12 (50%)> 7 cm 17/28 (60%)

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< 3 3-4 4-5 5-6 6-7 > 7PR

OPO

RTI

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WIT

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ETAS

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ISEA

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TUMOR SIZE

Metastatic Potential by Tumor Size

Ball et al AUA 201818

Institutional Experience

The vast majority of lesions that appear to be simple cysts on imaging are benign cysts on final path.

Complex cystic lesions are often low grade (Fuhrman 1-2) ccRCC on final path.

Patients who have developed metastatic disease have had large (> 3 cm) solid tumors.

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Cyst behavior

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Surveillance and Treatment

MRI: workhorse Ultrasound: adjunct

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MRI

Both T2 and T1 contrast enhanced phases are useful

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Clinic-Based Ultrasound

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Ultrasound Adjunct

> 3 cm

2.5 cm

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When to intervene

Most interventions are based on solid tumors (i.e. when solid tumor reaches 3 cm)

For mixed cystic lesions with a discrete nodule, the solid portion can be used as a trigger.

For mixed honeycomb-like lesions, the proportion of solid tumor can be estimated.

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Operative Consideration

Cyst decortication: not recommended

Enucleation Less parenchymal compression

Intraoperative ultrasound is critical

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Preoperative Planning

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Enucleation

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Operative Approach

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Acknowledgements Clinical Team: W. Marston Linehan, MD Ramaprasad Srinivasan, MD, PhD Cris Leite• Caitlin Drew, RN• Debbie Nielsen, RN• Lindsay Middleton, RN Clinical Fellow George Washington U Residents Georgetown U Residents Walter Reed Residents

Genetics Team• Laura Schmidt, PhD

• Cathy Vocke, PhD• Chris Ricketts, PhD

• Caitlin Drew, RN

• Debbie Nielsen, RN

• Lindsay Middleton, RN

Laboratory of Pathology Maria Merino, MD

Radiology Ashkan Malyeri, MD Rabindra Gautam Kailash Daryanani

Data Management

James Peterson

Kristin Choo

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